Alleviating antibiotic-induced gut dysbiosis by restoring small intestinal bile acid metabolism - PROJECT SUMMARY Antibiotic-induced damage to the natural flora of the human GI is associated with significant morbidity. As we advance more efficient strategies to fight the current antimicrobial resistance crisis, we must also develop therapeutic methodologies to reduce the collateral damage to the microbiome. Here we propose that the disruption of bile acid (BA) metabolism in the upper GI by antibiotics may contribute to antibiotic-induced dysbiosis (AID) in the lower GI and that correcting this may be a target for intervention. Host-produced BAs are vital to the stability of the microbiome and in defining metabolites available to the host and the lower GI. The host produces primary BAs that are deconjugated by bacteria with bile-salt hydrolase (BSH) enzymes in the small intestine (SI). Unconjugated BAs not reabsorbed by the host are modified into secondary BAs by microbes in the large intestine. Unconjugated and secondary bile acids can, in turn, modulate microbiome composition and activity by inhibiting the growth of certain bacteria and by changing nutrient availability. Research on antibiotics in the microbiome has mainly focused on fecal bacteria, leaving the impact of SI BA metabolism on AID largely unexplored. This lack of attention to upper GI bacteria and the spatial context of host-microbe interactions presents a significant obstacle to understanding AID. Our recent preliminary data showed that amoxicillin severely disrupts the SI microbiota. We also found that this disruption is associated with an almost complete reduction in the expression of BSH genes and BSH activity in the upper GI. A metabolomic analysis revealed that amoxicillin dramatically reduced unconjugated and secondary bile acids across GI regions. This is also associated with a reduction of lipids in the lower GI. Based on this data, we hypothesize that the depletion of microbial bile metabolism in the SI contributes to AID by altering BA-antimicrobial activity and microbial metabolism. The key goal of this application is to establish a causative link between the disruption of bile acid metabolism in the upper G.I. and amoxicillin-associated damage of the lower GI microbiome. Aim 1: Determine the role of BA metabolism in amoxicillin-induced gut dysbiosis. Aim 2: Evaluate the efficacy of BA restoration to control antibiotic-associated pathogens. Our ultimate goal is to develop novel prebiotic, probiotic, or pharmacological approaches to reduce the collateral impacts of antibiotics on the GI microbiota and prevent associated health burdens. Using matched multi-omic datasets we will uncover location-specific impacts of antibiotics over the entire length of the GI, enabling us to identify such intervention points. We envision that dietary supplements may be a particularly effective way to restore BA metabolism, and in this application, we test two such approaches.
